Potential effects of teriparatide (PTH (1–34)) on osteoarthritis: a systematic review

Osteoarthritis (OA) is a common and prevalent degenerative joint disease characterized by degradation of the articular cartilage. However, none of disease-modifying OA drugs is approved currently. Teriparatide (PTH (1–34)) might stimulate chondrocyte proliferation and cartilage regeneration via some uncertain mechanisms. Relevant therapies of PTH (1–34) on OA with such effects have recently gained increasing interest, but have not become widespread practice. Thus, we launch this systematic review (SR) to update the latest evidence accordingly. A comprehensive literature search was conducted in PubMed, Web of Science, MEDLINE, the Cochrane Library, and Embase from their inception to February 2022. Studies investigating the effects of the PTH (1–34) on OA were obtained. The quality assessment and descriptive summary were made of all included studies. Overall, 307 records were identified, and 33 studies were included. In vivo studies (n = 22) concluded that PTH (1–34) slowed progression of OA by alleviating cartilage degeneration and aberrant remodeling of subchondral bone (SCB). Moreover, PTH (1–34) exhibited repair of cartilage and SCB, analgesic, and anti-inflammatory effects. In vitro studies (n = 11) concluded that PTH (1–34) was important for chondrocytes via increasing the proliferation and matrix synthesis but preventing apoptosis or hypertrophy. All included studies were assessed with low or unclear risk of bias in methodological quality. The SR demonstrated that PTH (1–34) could alleviate the progression of OA. Moreover, PTH (1–34) had beneficial effects on osteoporotic OA (OPOA) models, which might be a therapeutic option for OA and OPOA treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02981-w.


Background
Osteoarthritis (OA) is a common musculoskeletal disorder and prevalent degenerative disease worldwide [1,2]. Both non-load bearing and load-bearing joints are affected by multiple factors such as trauma, senility, gender, genetics, and obesity [3], which resulted in functional disability or decreased quality of life. Articular cartilage is an avascular tissue, while chondrocytes are unique cellular components and responsible for the maintenance of the extracellular matrix (ECM) via the balance of catabolism and anabolism. Type II collagen (COL II) and aggrecan (AGC) are secreted proteins, which are essential for the integrity of cartilage. Break-down of chondrocytes is one of the molecular characteristics of OA, which is characterized by progressive damage including cartilage erosion, synovitis, and subchondral bone (SCB) disturbance. The normal metabolism of cartilage is disturbed by inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), shifting to catabolism and ECM degradation [4]. Oxidative stress and apoptosis generate the decrease of chondrocytes and loss of cartilage [5]. The schematic diagram of normal and osteoarthritic joint was illustrated in Fig. 1.
Recommendation of OA treatment includes physiotherapy, pharmacological, and surgical interventions [6,7]. Physiotherapy should be advocated due to its safety and effectiveness. However, limited choices and less effectiveness of drugs were restricted to symptom relief and accompanied by adverse effects [8]. Currently, no disease-modifying OA drugs (DMOADs) are available to alleviate the progression of OA. And therefore, Fig. 1 The schematic structures of normal (left part) and osteoarthritic (right part) joint. Multiple factors and pro-inflammatory cytokines resulting chondrocytes catabolism and ECM degradation in OA joints strategies to protect the chondrocytes and the cartilage represent potential new therapeutic modalities.
Teriparatide (PTH ) contains 34 amino acids of parathyroid hormone, which was applied on the treatment of osteoporosis (OP) and bone fracture [9,10] by maintaining calcium homeostasis, increasing cortical and trabecular thickness, and stimulating bone formation [11]. In addition, quantitative studies documented PTH  could mediate anabolic effects among chondrocytes [12] by enhancing chondral regeneration [13] and increasing ECM synthesis [14]. Experimental studies investigated the benefits of PTH (1-34) on OA pitiful without frequent practice or systematic review (SR). For these reasons, we reviewed the accessible research to update the effect of PTH (1-34) on OA.

Protocol
We performed this SR in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements [15]. We recorded the study protocol on the international Prospective Register of Systematic Reviews (PROSPERO) with code CRD42022315089.

Inclusion and exclusion criteria
The eligible studies should meet the following criteria: (1) prospective and retrospective studies, randomized and controlled clinical trials; (2) patients or animal models with OA treated by PTH (1-34) directly or indirectly; and (3) studies published in the English language. Studies were excluded from this review if they were reviews, research protocols, abstracts only, commentaries, or editorials.

Study selection
All records of five databases were imported into the reference management software program Endnote X 9.3.3. After the removal of duplicates, two authors (GQL and SL) independently reviewed the titles and abstracts of the remaining records for relevance to the topic. Studies that potentially or completely met the inclusion criteria were kept and full texts were retrieved. The two authors (GQL and SL) independently assessed the full texts to decide whether to keep the records or not. A consensus meeting with a third reviewer (FY) was used to resolve discrepancies. The final included studies were reviewed by all authors for agreement.

Data extraction
The information of in vivo and in vitro studies was extracted in the standardized information forms: (1) first author's surname, year of publication, and country; (2) subjects; (3) intervention; (4) dose and duration of treatment; (5) route; and (6) findings. Two investigators (GQL and SL) independently reviewed and extracted information from included studies. Disagreements were discussed with a third author (JW) to reach a consensus.

Quality assessment
The methodological quality of the in vivo studies was assessed by SYRCLE's risk of bias tool [16] while the in vitro studies with Checklist for Reporting In-vitro Studies (CRIS) instruction [17]. Two authors (GQL and SL) independently assessed the methodological quality of the articles included, and discrepancies were resolved by discussion with a third author (FY).

In vivo studies showed potential effects of PTH (1-34) on OA models
According to the inclusion criteria, 22 in vivo studies were included (    injection suppressed early stages of OA in papaininduced OA (PIOA) rats [22]. Chen et al. suggested that PTH (1-34) improved spontaneous OA by directly affecting the cartilage rather than the SCB or metaphyseal bone [43], reduce chondrocyte terminal differentiation and apoptosis, and increase autophagy on ACLT rats via IA injection [44]. Longo et al. concluded that PTH (1-34) promoted the regenerative and chondroprotective effects of the tissue-engineered meniscus by inhibiting the differentiation of mesenchymal stem cells (BMSC) chondrogenesis and cartilage degeneration among the meniscectomy dogs [30], which represented a promising method to increase the chance of regeneration in the tissue-engineered meniscus.

In vitro studies showed potential mechanism of PTH (1-34) intracellularly
Based on the inclusion criteria, 11 in vitro investigations were included in the SR (     increased the proliferation of chondrocytes from human and RA patients [49]. However, Funk et al. revealed that the PTHrP could be examined in synovium and synoviocytes obtained from RA patients, which help to clarify the pathogenesis of RA to a certain extent and remain to be investigated further [48]. In addition, Lugo et al. found that PTH (1-34) ameliorated OA by improving SCB integrity, inhibiting cartilage degradation, and exerting effects on synovial changes [38]. PTH (1-34) held potential therapeutic option for synoviopathy associated with OA.

Quality assessment of included studies
Methodological quality was assessed for all 33 involved studies (Fig. 3). An unclear risk of selection bias (because of lacking data regarding randomization method: n = 16); detection bias (blinding of outcome assessment, n = 20); performance bias (because of absent data about blinding of subjects, n = 11), attrition bias (n = 17), reporting bias (n = 21), and other bias (n = 15) were found.

Discussion
To our knowledge, this is the first SR evaluating the existing papers about the effect of PTH (1-34) on OA regarding in vivo and in vitro investigations. The chondro-protective and cartilage-regenerative effects were reviewed, indicating that PTH (1-34) might be a potential preventative and therapeutic treatment for OA. OA is the most prevalent degenerative joint disease with complicated pathogenesis characterized with damage to cartilage, narrow synovial cavity, invasion of the SCB, formation of osteophytes, and synovitis [57]. OP is a metabolic bone disease with decreased bone strength but increased fracture risk. OP and OA are common clinical conditions with high prevalence among older adults. Antiresorptive agents exhibited effects on bone mineralization and cartilage degradation for OA or OPOA [58]. However, treatments with polypharmacy for OA are limited to pain relief with less effective, which should be individualized to reduce the risk of side effects [59]. And therefore, DMOADs are highly demanded for OA or OPOA.
Quantitative studies indicated that PTH (1-34) played a significant role in calcium metabolism with an anabolic effect in the treatment of OP, fracture healing, non-union and stress fracture, augmentation of implant fixation, and chondro-protection in OA [14,60]. In addition, PTH (1-34) could be a systemic pharmacology for OA by influencing cartilage quality such as ECM and chondrocyte contents [61]. The effects of PTH  were involved in decreasing COLX or RUNX2 but increasing AGC [34], which not only inhibited matrix metallopeptidase 13 (MMP13) or ADAM metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS4), but also enhanced COLII and AGC [26,42]. Moreover, PTH (1-34) reversed terminal differentiation towards hypertrophy and decreased apoptosis of chondrocytes [46,47].
In addition, the attenuation of signaling pathways including oxidative stress and apoptosis had an indispensable role in OA. Autophagy was a protective mechanism in normal cartilage. PTH (1-34) alleviated OA progression by reducing terminal differentiation, reducing apoptosis, and increasing autophagy via the mechanistic target of rapamycin (mTOR) and p62 [21]. Apoptosis was reversed, while both Bcl-2 and Bax were upregulated by PTH . Moreover, PTH (1-34) might reduce the accumulation of senescent cells by inhibiting p16 [28]. Both the sustained and intermittent action of PTH (1-34) suppressed OA effectively [22,65]. IA application would directly affect the cartilage rather than the SCB or metaphyseal bone [43]. PTH (1-34) inhibited the terminal differentiation of human chondrocytes in vitro and inhibits OA progression in rats in vivo [25]. PTHrP was up-regulated and mediated by calcium-sensing receptor in OA cartilage, which might promote both proliferation of chondrocyte and osteophyte formation [66]. Stimulation of focal osteochondral defect, enhancement of allograft bone union, and differentiation of MSCs are various effects of PTH  in tissue engineering [32,67].
An ideal DMOAD can not only repair and regenerate cartilage, but also alleviate inflammation of synovium and pain. Healthy synovial joints are capable of maintaining extraordinary lubrication, attributed to structures as well as the cellular constitutions. However, both synovitis and OP contributed to cartilage degradation [68] but all pathology above could be suppressed by PTH (1-34) [69]. Impairment of SCB aggravated cartilage damage in early OPOA rabbits [39] and is associated with weight-bearing pain [70]. Overall, PTH (1-34) exhibited protective effects on the change of synovitis as well as pain relief.
Clinically, resorption played a significant role while PTH (1-34) was a reasonable option for OP patients [71]. Successful osteoanabolic treatment with PTH (1-34) benefited symptomatic stress concentration with completely stem tip pain-free [72]. The periprosthetic BMD was preserved after total hip arthroplasty (THA) [73] while bone ingrowth was promoted after total knee arthroplasty (TKA) [74] enforced by PTH . In addition, nonunion of periprosthetic fracture   were explained by multiple mechanisms after TKA benefited from PTH (1-34) as well [75]. However, early mineralization of the MCC caused by PTH (1-34) might shift modifications of the subarticular spongiosa. Overall, we had better use the PTH  in proper situations and dosages.
There are some limitations in our current review. Firstly, the present review cannot identify the mechanisms accounting for the precious mechanism of PTH (1-34) on OA. Further research evidence is needed to deepen our current review. Secondly, although a thorough search was performed from five English databases, some pertinent studies may still have been missed. Thirdly, limited information in the current reviewed investigations is an urgent call for subsequent studies to confirm the findings based on additional information. Finally, there are only included studies published in English; thereby, some studies in other languages would be missed out.

Conclusion
In conclusion, the SR, which included both in vivo and in vitro studies, described the beneficial effects of PTH (1-34) on OA via alleviating cartilage damage progression, inhibiting the abnormal SCB remodeling, suppressing synovitis, reducing oxidative stress or apoptosis of chondrocytes, and elevating autophagy. Some of the OA or OAOP patients might benefit from PTH (1-34) as well. The present SR is a description of existing studies regarding the effectiveness of PTH (1-34) administration in OA together with mechanisms, which suggested the necessity for further clinical trials and animal investigations to achieve concise conclusions about the effects of PTH (1-34) on OA.